An occurrence of peripheral neuropathy is caused by a disorder which provides damage directly on neural tissues or affects neural tissues. Depending on the type of neural tissues that are affected, peripheral neuropathy can be categorized into sensory neuropathy, motor neuropathy, and autonomic neuropathy. In case of sensory neuropathy, a patient may feel numbness to touch, shaking, a reduced ability to sense temperature change, tingling feeling, or burning pain, and also skin allodynia or the like. Meanwhile, motor neuropathy is accompanied with impaired balance, weakness of muscle strength, and a patient with autonomic neuropathy experiences, depending on an organ affected by corresponding neuron, urinary incontinence due to weakened bladder controlling activity, or has abnormal blood pressure and heartbeat (R. A. Hughes, 2002, BMJ, v324, pp 466-469; J. M. Torpy et al., 2010, JAMA, v303, p 1556).
Various factors have been suggested as a cause of peripheral neuropathy, such as genetic disorders, metabolic or endocrine disorders, inflammatory disorders, malnutrition like vitamin deficiency, and anti-cancer agents administered during cancer treatment. Among them, chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect that may reduce the dosage of the anti-cancer agent administered to a patient depending on severity of symptoms or, in an extreme case, may early terminate the anti-cancer therapy, which negatively affect anti-cancer therapy. It is known that about one third of patients receiving anti-cancer therapy are affected by CIPN, and one third of the patients with CIPN have a permanent neuronal damage (A. Bhagra and R. D. Rao, 2007, Curr Oncol Rep, v9, pp 290-299). The symptoms related to CIPN include numbness in fingers and toes, tingling or burning feeling, cold feeling, pain, and weakened touch sense and muscle strength (T. Armstrong et al., 2005, Oncol Nurs Forum, v32, pp 305-311; C. Visovsky et al., 2008, Clin J Oncol Nurs, v12, pp 243-247).
Anti-cancer agents which are known to cause CIPN include platinum-based anti-cancer agents, taxane-based anti-cancer agents, vinca alkaloids, bortezomib, thalidomide, or the like. The incidence of CIPN is about 20-75% depending on types, dosages, and administration periods of an anti-cancer agents (G. Cavaletti et al., 2011, Curr Treat Options Neurol, v13, pp 180-190). Until now the clear mechanism of neuronal toxicity mediated by an anti-cancer agent has not been elucidated. It has been just presumed that the mechanism underlying cytotoxicity of anti-cancer agents in common cancer cells may be similar to that underlying neuronal toxicity in peripheral nervous system. It is known that the anti-cancer agent administered to a patient is accumulated not only in tumor tissues but also in peripheral nervous system where it exerts neuronal toxicity and induces CIPN.
Until now, there is no standard therapeutic agent available which has been approved by US FDA for CIPN treatment. Anti-seizure agents like gabapentin or anti-depressants like amitriptyline are clinically used to alleviate CIPN-related symptoms. However, large scale clinical studies have failed to prove their efficacy for CIPN treatment. Furthermore, those drugs basically exhibit adverse side effects like dizziness, sleepiness, or the like, and have a disadvantage that administration at high dose is impossible due to their low safety margin. Such medical unmet needs make it urgent to develop a novel safer and more effective therapeutic or preventive agent of CIPN. Because CIPN is considered a complex disease, a multi-target-based drug development may be more appropriate, and thus medicinal plants or natural products which have been traditionally used can be important starting materials from the viewpoint of drug development strategy.
Lithospermi Radix is a root of Boraginaceae including Lithospermum erythrorhizon Siebold et Zuccarini, Arnebia euchroma Johnst and Arnebia guttata Bunge. It has a thin and spindle-like shape with irregular branches, and the length is 6 to 10 cm and the diameter is 5 to 15 mm. The outer surface of Lithospermi Radix has dark purple to purplish brown color, and the skin is rough and easily removable. There are usually twisted vertical grooves, which sometimes reach the neck part. On top of the root, stem hairs are sometimes present. Lithospermi Radix is easily broken, and the cross-section of broken root shows granular shape with many voids. When observed under a magnifier, the horizontal cross-section shows dark purple color on outer skin and the soft brown part inside the cross-section is randomly present. The neck part has yellowish color, and the center of the top part sometimes has voids of which periphery exhibits reddish purple color. Lithospermi Radix has unique mild smell and tastes rather sweet. It is used as a purple dye and known to have effects of lowering body heat, clarifying blood, and improving blood circulation. In Korean Patent Registration No. 0558159, a method to produce health supplement using Lithospermi Radix is disclosed which has an excellent effect on recovery of fatigue and growth of children. Furthermore, in Korean Patent Application Publication No. 2015-0047173, a composition comprising a Lithospermi Radix extract as an effective component is disclosed which is used for preventing or alleviating invasive inflammation in lungs caused by metastasis of acute pancreatitis. However, a technique related to use of Lithospermi Radix for peripheral neuropathy has not been reported yet.